Circulating blood cell counts represent important intermediate phenotypes for a variety of cardiovascular, pulmonary, hematologic, and immunologic diseases. These traits differ by ethnicity and studying the genetics of these quantitative blood traits in African Americans (AAs) may reveal new biologic pathways that ultimately contribute to our understanding both of biology of blood cell production and of the relationship of blood counts with CVD and other chronic diseases that disproportionately impact AAs. Genome-wide association studies (GWAS), to date, performed mainly in European Americans, have implicated a number of genomic loci. Despite these successes, association signals for blood cell traits are often associated with uncertain effects on gene function or regulation, and therefore not readily translatable to clinical practice or treatment. Several recen advancements hold promise for translating genetic association findings for blood cell traits into mechanism-based therapeutic approaches for clinical disease. First, genome-wide mapping of blood cell type- and lineage-specific promoter and enhancer elements, transcription factor binding patterns and epigenetic profiling now provide a detailed picture of the cis- and trans- regulatory landscape during hematopoiesis. Second, experimental approaches utilizing genome engineering (RNA- guided CRISPR-Cas9) can characterize critical regulatory elements and functional variants of modest effect that are essential for stage-specific, lineage-restricted effects on gene expression. This proposal will utilize the wealth of newly available genetic data in multiple large AA cohorts, including exome array data on ~11,400 participants from the REasons for Geographical And Regional Differences in Stroke (REGARDS), the Jackson Heart (JHS) and Women's Health Initiative (WHI) studies and high-coverage whole genome sequence (WGS) data available on ~3,500 JHS participants through a recent NHLBI-funded WGS initiative to discover and functionally characterize novel genetic associations. These data will be combined with existing GWAS and exome array data on thousands of additional AAs with measured blood cell traits to form the largest and most comprehensive genetic study of blood cell traits ever conducted in AAs. Our study will use novel and established analytic and experimental approaches, consistent with the goals and directives of this initiative, to identify important genetic variants affecting these important blood-based biomarkers.